Many complementary and alternative medicine (CAM) approaches for cancer have been proposed to reduce "oxidative stress" i host cells and/or in cancer cells. New data have revealed that defective genes encoding DNA mismatch repair (MMR) enzymes and glutathione S-transferases (GSTs), known to contribute to the pathogenesis of many common human cancers, cause a phenotype of "oxidation tolerance," an increased propensity for cells to survive oxidative stress despite high levels of oxidative genome damage. Treatment with anti-oxidants, including the many anti-oxidant strategies offered by CAM, might directly target this phenotype of "oxidation tolerance" and attenuate oxidative genome damage associated with carcinogenesis. Of potential CAM benefit, low doses of multiple component anti-oxidants, characteristics of CAM treatments, might be superior to high doses of single anti-oxidants, characteristics of CAM treatments, might be superior to high doses of single anti-oxidants, characteristic of conventional medicine. Of CAM concern, most "anti-oxidants" can display "pro-oxidant" activity in certain contexts, resulting in potentially harmful CAM effects. This proposal embodies a mechanistic assessment of the effects of neuroendocrine stress and of PC-SPES on oxidative genome damage in cells containing MMR enzyme and GST gene defects. The hypothesis that CAM interventions can reduce oxidative stresses leading to oxidative genome damage in "oxidation tolerant" will be tested be: (1) assessing the contribution of host neuroendocrine stress to oxidative DNA damage in human breast (BCA) and prostate (PCA) cancer cells carrying defective GSTP1 alleles, (2) determining the effects of neuroendocrine stress on oxidative DNA damage in different organs in mice carrying disrupted Gstp and Msh2 alleles, (3) characterizing the effects of treatment with PC SPES on oxidative DNA damage in human PCA cells, (4) evaluating the effects of PC-SPES treatment on oxidative DNA damage in mice with Gstp and Msh2 defects, and (5) exploring the effects of PC-SPES treatment on changes in gene expression in vivo in human PCA cells.